Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

Jonathan P Gumucio, Austin H Qasawa, Patrick J Ferrara, Afshan N Malik, Katsuhiko Funai, Brian McDonagh, Christopher L Mendias

Preprint posted on November 18, 2018

Why do lipids accumulate following muscle injury? A multi-omics study points to mitochondrial and lipid metabolism dysfunction.

Selected by Pablo Ranea Robles


Do you know anyone that had a muscle injury while heavy lifting or practicing sports? Sure you do. Chronic muscle injuries provoke the loss of mobility in the patients, imposing a burden on health care and workers’ compensation systems. Among the muscles usually prone to injury, the rotator cuff is one of the most affected. The rotator cuff is a group of muscles and tendons that stabilize the shoulder joint and let us lift and rotate our arms (Figure 1).

Rotator cuff anatomy

Figure 1. The anatomy of the human rotator cuff. Credit: Harvard Health Publishing


Have you ever wondered what changes happen in that injured muscle after the injury? One of the best characterized effects of muscle injury is pathological lipid accumulation. This is known as myosteatosis (from the Greek words myos-, muscle, steatos-, fat, and -osis, formation). The rotator cuff is particularly susceptible to develop pathological lipid accumulation after injury.  Importantly, lipid accumulation in this muscle after injury correlates with a poor outcome after surgical repair (Gladstone et al., 2007). Moreover, recurrence of tears after the injury is quite common in this type of injuries (Isaac et al., 2012). It is known that lipid excess likely impairs muscle regeneration, but the mechanisms driving lipid accumulation in myosteatosis remain largely unknown.

In this study, Gumucio and coworkers used a rat model of rotator cuff injury (Gumucio et al., 2018). The anatomy of the rotator cuff in rats is similar to humans, and this model mimics many of the pathological changes observed in patients with chronic rotator cuff tears (Soslowsky et al., 1996). They studied the supraspinatus muscle, one of the muscles of the rotator cuff (supraspinatus, infraspinatus, teres minor, and subscapularis). Experimental groups were uninjured and injured rats, either 10, 30, or 60 days after the injury. They aimed to characterize the biochemical and cellular pathways that lead to myosteatosis after skeletal muscle injury.

Key findings

They characterized the changes in muscle fiber force production and the biological changes after injury by the integration of different -omics techniques. They evaluated alterations in the rotator cuff transcriptome (by RNA sequencing), proteome, metabolome, and lipidome (using mass spectrometry). The main outcome was the identification of mitochondrial dysfunction and impaired fatty acid oxidation as strong drivers of the pathological steatosis after muscle injury. Then, they studied in detail the hypothesis that mitochondrial dysfunction drives pathological lipid accumulation in torn rotator cuff muscles.

Shotgun lipidomics revealed expected increases in different lipid species at different time points in the injured muscles, such as free fatty acids (FFA), triglycerides, ceramides, sphingomyelins, and some phospholipids. Other lipids displayed a biphasic response, like cholesterol esters, diacylglycerides, and other phospholipids.

The metabolomics data revealed a decrease in nucleoside and nucleotide metabolites, concomitant with an increase in glycolytic and pentose phosphate pathway metabolites. The transcriptomics data showed an induction of well-known pathways in muscle injury, such as autophagy, atrophy, inflammation or fibrosis. It is worth to highlight the decreased mRNA expression of genes involved in mitochondrial function (Krebs cycle and OXPHOS system), lipid uptake and metabolism, and fatty acid oxidation, which was confirmed by proteomics data. Another aspect that appeared in the transcriptomics and proteomics data is oxidative stress. This is deduced due to the increase reactive oxygen species (ROS)-related genes and proteins amount. Moreover, omega-oxidation and peroxisomal metabolism were induced, since transcriptomics data showed augmented expression of Acox1 (Acyl-CoA oxidase 1, an enzyme of peroxisomal beta-oxidation) and Cyp4b1 (from the cytochrome P450 family, related to omega-oxidation of fatty acids). These pathways are usually active when mitochondrial fatty acid oxidation is impaired. These data, together with the increased glycolytic metabolites point to a metabolic shift in injured muscles, from fatty acid oxidation and oxidative phosphorylation to glycolysis.

Finally, a deeper study on mitochondrial function demonstrated that mitochondrial metabolism is impaired in injured muscles, as shown by a reduction in the activity of complexes I, II, and IV, an increase of some antioxidant proteins, and a reduction in the oxidation rate of pyruvate and palmitate. However, mitochondrial content seems to be equal in injured and non-injured muscles, since mitochondrial DNA levels were similar in both groups.

Future directions and questions for authors

Some aspects of this study deserve more attention. For instance, what is the shape of mitochondria in injured muscles? Are they smaller or bigger? Is there peroxisomal proliferation in injured muscles, given the increase of peroxisomal metabolism? Which are the species of acylcarnitines measured? If fatty acid oxidation is impaired, one would expect an increase in some of the acylcarnitines species. Is there autophagy impairment in the injured muscles? The p62 accumulation observed in injured muscles is a classical marker of autophagy impairment. After this study, it would be of interest to know which the next steps are. Can these altered pathways be modulated by drugs? In this way, we would be able to study their effect on muscle regeneration after injury. It would be also of interest to compare human samples from injured muscles with non-injured muscles, to see if these changes are conserved. Finally, one important weakness of this study is that it has been performed only in male rats. Fat content and metabolism is different between men and women, so more studies in female individuals of animal models need to be done to fully understand the pathophysiology of muscle injuries.

What I liked about the study

I liked that the authors integrated different -omics data to gain insights into the molecular physiology of muscle injury. This kind of unbiased approach can shed light on hidden pathological mechanisms. Here, they uncovered a central role of mitochondrial and lipid metabolism in the development of myosteatosis after muscle injury.



Gladstone, J. N., Bishop, J. Y., Lo, I. K. Y. and Flatow, E. L. (2007). Fatty Infiltration and Atrophy of the Rotator Cuff do not Improve after Rotator Cuff Repair and Correlate with Poor Functional Outcome. Am. J. Sports Med. 35, 719–728.

Gumucio, J. P., Qasawa, A. H., Ferrara, P. J., Malik, A. N., Funai, K., McDonagh, B. and Mendias, C. L. (2018). Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis. bioRxiv 471979.

Isaac, C., Gharaibeh, B., Witt, M., Wright, V. J. and Huard, J. (2012). Biologic approaches to enhance rotator cuff healing after injury. J. shoulder Elb. Surg. 21, 181–90.

Soslowsky, L. J., Carpenter, J. E., DeBano, C. M., Banerji, I. and Moalli, M. R. (1996). Development and use of an animal model for investigations on rotator cuff disease. J. shoulder Elb. Surg. 5, 383–92.

Tags: lesion, muscular, rehabilitation

Posted on: 7th January 2019

Read preprint (No Ratings Yet)

  • Have your say

    Your email address will not be published. Required fields are marked *

    This site uses Akismet to reduce spam. Learn how your comment data is processed.

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    Also in the biochemistry category:

    HIV-1 Gag specifically restricts PI(4,5)P2 and cholesterol mobility in living cells creating a nanodomain platform for virus assembly

    C. Favard, J. Chojnacki, P. Merida, et al.

    Selected by Amberley Stephens

    Aqueous synthesis of a small-molecule lanthanide chelator amenable to copper-free click chemistry

    Stephanie Cara Bishop, Robert Winefield, Asokan Anbanandam, et al.

    Selected by Zhang-He Goh

    Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity

    Marion Regnier, Arnaud Polizzi, Sarra Smati, et al.

    Selected by Pablo Ranea Robles

    Microfluidic protein isolation and sample preparation for high resolution cryo-EM

    Claudio Schmidli, Stefan Albiez, Luca Rima, et al.

    Selected by David Wright


    Vincent Mercier, Jorge Larios, Guillaume Molinard, et al.

    Selected by Nicola Stevenson


    Dynamic Aha1 Co-Chaperone Binding to Human Hsp90

    Javier Oroz, Laura J Blair, Markus Zweckstetter

    Selected by Reid Alderson


    A DNA-based voltmeter for organelles

    Anand Saminathan, John Devany, Kavya S Pillai, et al.

    Selected by Robert Mahen


    Structures of the Otopetrin Proton Channels Otop1 and Otop3

    Kei Saotome, Bochuan Teng, Che Chun (Alex) Tsui, et al.

    Selected by David Wright

    Inactive USP14 and inactive UCHL5 cause accumulation of distinct ubiquitinated proteins in mammalian cells

    Jayashree Chadchankar, Victoria Korboukh, Peter Doig, et al.

    Selected by Mila Basic

    S-acylated Golga7b stabilises DHHC5 at the plasma membrane to regulate desmosome assembly and cell adhesion.

    Keith T Woodley, Mark O Collins

    Selected by Abagael Lasseigne


    A complex containing lysine-acetylated actin inhibits the formin INF2

    Mu A, Tak Shun Fung, Arminja N. Kettenbach, et al.

    Selected by Laura McCormick


    Super-resolution Molecular Map of Basal Foot Reveals Novel Cilium in Airway Multiciliated Cells

    Quynh Nguyen, Zhen Liu, Rashmi Nanjundappa, et al.

    Selected by Robert Mahen

    Atlas of Subcellular RNA Localization Revealed by APEX-seq

    Furqan M Fazal, Shuo Han, Pornchai Kaewsapsak, et al.


    Proximity RNA labeling by APEX-Seq Reveals the Organization of Translation Initiation Complexes and Repressive RNA Granules

    Alejandro Padron, Shintaro Iwasaki, Nicholas Ingolia

    Selected by Christian Bates

    Applications, Promises, and Pitfalls of Deep Learning for Fluorescence Image Reconstruction

    Chinmay Belthangady , Loic A. Royer

    Selected by Romain F. Laine

    Activation of intracellular transport by relieving KIF1C autoinhibition

    Nida Siddiqui, Alice Bachmann, Alexander J Zwetsloot, et al.

    Selected by Ben Craske, Thibault Legal and Toni McHugh


    Integrated NMR and cryo-EM atomic-resolution structure determination of a half-megadalton enzyme complex

    Diego Gauto, Leandro Estrozi, Charles Schwieters, et al.

    Selected by Reid Alderson


    Also in the physiology category:

    Optical determination of absolute membrane potential

    Julia R. Lazzari-Dean, Anneliese M.M. Gest, Evan Miller

    Selected by James Marchant

    Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity

    Marion Regnier, Arnaud Polizzi, Sarra Smati, et al.

    Selected by Pablo Ranea Robles

    A DNA-based voltmeter for organelles

    Anand Saminathan, John Devany, Kavya S Pillai, et al.

    Selected by Robert Mahen


    Quantification of microenvironmental metabolites in murine cancer models reveals determinants of tumor nutrient availability

    Mark R Sullivan, Laura V Danai, Caroline A Lewis, et al.

    Selected by Maria Rafaeva


    Regulation of modulatory cell activity across olfactory structures in Drosophila melanogaster

    Xiaonan Zhang, Kaylynn Coates, Andrew Dacks, et al.

    Selected by Rudra Nayan Das


    EHD2-mediated restriction of caveolar dynamics regulates cellular lipid uptake

    Claudia Matthaeus, Ines Lahmann, Severine Kunz, et al.

    Selected by Andreas Müller


    Super-resolution Molecular Map of Basal Foot Reveals Novel Cilium in Airway Multiciliated Cells

    Quynh Nguyen, Zhen Liu, Rashmi Nanjundappa, et al.

    Selected by Robert Mahen

    Defining the design requirements for an assistive powered hand exoskeleton

    Quinn A Boser, Michael R Dawson, Jonathon S Schofield, et al.

    Selected by Joanna Cross

    Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

    Jonathan P Gumucio, Austin H Qasawa, Patrick J Ferrara, et al.

    Selected by Pablo Ranea Robles

    The Toll pathway inhibits tissue growth and regulates cell fitness in an infection-dependent manner

    Federico Germani, Daniel Hain, Denise Sternlicht, et al.

    Selected by Rohan Khadilkar

    Optogenetic manipulation of medullary neurons in the locust optic lobe

    Hongxia Wang, Richard B. Dewell, Markus U. Ehrengruber, et al.

    Selected by Ana Patricia Ramos

    Targeting light-gated chloride channels to neuronal somatodendritic domain reduces their excitatory effect in the axon

    Jessica Messier, Hongmei Chen, Zhao-Lin Cai, et al.


    High-efficiency optogenetic silencing with soma-targeted anion-conducting channelrhodopsins

    Mathias Mahn, Lihi Gibor, Katayun Cohen-Kashi Malina, et al.

    Selected by Mahesh Karnani


    Rearing temperature and fatty acid supplementation jointly affect membrane fluidity and heat tolerance in Daphnia

    Dominik Martin-Creuzburg, Bret L. Coggins, Dieter Ebert, et al.

    Selected by Alexander Little

    Long-term live imaging of the Drosophila adult midgut reveals real-time dynamics of cell division, differentiation, and loss

    Judy Martin, Erin Nicole Sanders, Paola Moreno-Roman, et al.

    Selected by Natalie Dye

    Individual- and population-level drivers of consistent foraging success across environments

    Lysanne Snijders, Ralf HJM Kurvers, Stefan Krause, et al.

    Selected by Rasmus Ern

    Zebrafish as a model to investigate the effects of exercise in cancer

    Alexandra Yin, Nathaniel R. Campbell, Lee W. Jones, et al.

    Selected by Jacky G. Goetz